Pheochromocytomas are uncommon tumors that are exceedingly dangerous and difficult to diagnose. To improve diagnostic accuracy, we recently developed a new technique for measuring plasma concentrations of free metanephrines, using HPLC and electrochemical detection. Our original study, in 52 patients with pheochromocytoma and 191 normals or patients with other disorders, indicated that the sensitivity of plasma metanephrines for pheochromocytoma was 100% and the negative predictive value of normal plasma concentrations of metanephrines was also 100%. We continue to use this test, along with other standard tests, in the screening of patients for pheochromocytoma. We are evaluating patients with hereditary pheochromocytoma, especially von Hippel-Lindau disease (VHL), on a regular schedule to determine when plasma metanephrines become positive in comparison to the other tests for this tumor. Preliminary results indicate that the pheochromocytoma in such affected kindreds, when first detected, is only weakly functional and asymptomatic. With time, it becomes more active biochemically, and symptomatic. Thus, diagnosis becomes more certain with time, but so is the risk of an adverse outcome. Therefore, VHL kindreds, particularly those with a history of pheochromocytoma, must be carefully and repeatedly screened to prevent the potential morbidity and mortality from an undiagnosed pheochromocytoma.